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神经系统疾病中的染色质改变及(表观)基因组拯救策略

Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue.

作者信息

Janowski Marcin, Milewska Małgorzata, Zare Peyman, Pękowska Aleksandra

机构信息

Dioscuri Centre for Chromatin Biology and Epigenomics, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Pasteur Street, 02-093 Warsaw, Poland.

出版信息

Pharmaceuticals (Basel). 2021 Aug 4;14(8):765. doi: 10.3390/ph14080765.

Abstract

Neurological disorders (NDs) comprise a heterogeneous group of conditions that affect the function of the nervous system. Often incurable, NDs have profound and detrimental consequences on the affected individuals' lives. NDs have complex etiologies but commonly feature altered gene expression and dysfunctions of the essential chromatin-modifying factors. Hence, compounds that target DNA and histone modification pathways, the so-called epidrugs, constitute promising tools to treat NDs. Yet, targeting the entire epigenome might reveal insufficient to modify a chosen gene expression or even unnecessary and detrimental to the patients' health. New technologies hold a promise to expand the clinical toolkit in the fight against NDs. (Epi)genome engineering using designer nucleases, including CRISPR-Cas9 and TALENs, can potentially help restore the correct gene expression patterns by targeting a defined gene or pathway, both genetically and epigenetically, with minimal off-target activity. Here, we review the implication of epigenetic machinery in NDs. We outline syndromes caused by mutations in chromatin-modifying enzymes and discuss the functional consequences of mutations in regulatory DNA in NDs. We review the approaches that allow modifying the (epi)genome, including tools based on TALENs and CRISPR-Cas9 technologies, and we highlight how these new strategies could potentially change clinical practices in the treatment of NDs.

摘要

神经疾病(NDs)是一组影响神经系统功能的异质性疾病。NDs通常无法治愈,会对患者的生活产生深远且有害的影响。NDs病因复杂,但通常具有基因表达改变和关键染色质修饰因子功能异常的特征。因此,靶向DNA和组蛋白修饰途径的化合物,即所谓的表观遗传药物,是治疗NDs的有前景的工具。然而,针对整个表观基因组可能不足以改变特定基因的表达,甚至对患者健康而言是不必要且有害的。新技术有望扩大对抗NDs的临床工具库。使用设计核酸酶(包括CRISPR-Cas9和TALENs)进行(表观)基因组工程,有可能通过在遗传和表观遗传水平上靶向特定基因或途径,以最小的脱靶活性来帮助恢复正确的基因表达模式。在此,我们综述表观遗传机制在NDs中的作用。我们概述由染色质修饰酶突变引起的综合征,并讨论NDs中调控DNA突变的功能后果。我们综述了能够修饰(表观)基因组的方法,包括基于TALENs和CRISPR-Cas9技术的工具,并强调这些新策略如何有可能改变NDs治疗中的临床实践。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e46f/8399958/5bf3ba1feb1b/pharmaceuticals-14-00765-g001.jpg

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